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In the April 2021 blog “Could High-Dose Thiamine (B-1) Help with ME/CFS, Fibromyalgia, and the Neurological Complications of Ehlers-Danlos Syndrome?” I reported on the findings of a randomized controlled trial of high-dose thiamine (for people with quiescent inflammatory bowel disease), offered several hypotheses for why high-dose thiamine might have positive effects, and speculated that it might be helpful for people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia and Ehlers-Danlos Syndrome (EDS).

Could High-Dose Thiamine (B-1) Help with ME/CFS, Fibromyalgia, and the Neurological Complications of Ehlers-Danlos Syndrome?

To gather more evidence on the potential of high-dose thiamine for people in our communities, I asked Health Rising readers who had taken high-dose thiamine in the past to complete a survey.  Fifty Health Rising readers responded – thank you! – leading to a total of 55 responses that met the criteria for inclusion in this retrospective study, including a handful gathered earlier from other sources.  I report here on the results of the survey.

First a few caveats.

Of the 55 respondents, 49 report having ME/CFS, 20 report having fibromyalgia, and 12 report having EDS.  However, the sample is not representative of the overall population of individuals with these conditions, and thus no definitive conclusions can be drawn.  Moreover, as we have learned the hard way over the years, some treatments that seem to be effective based on retrospective recollection do not end up being effective when subjected to rigorous evaluation.

The survey results should thus be understood for what they are – an initial indication of the potential of high-dose thiamine that needs to be confirmed through rigorous research.  Hopefully, these results will help prompt a large, randomized study that could definitively assess whether high-dose thiamine is effective in relieving fatigue, post-exertional malaise, brain fog, and other symptoms.

Overall Results

Caveats aside, the results are striking.  More than three-quarters of respondents report that high-dose thiamine has helped them either “a great deal” (48.1 percent) or “somewhat” (29.6 percent).  Since some of the respondents who say high-dose thiamine helped them somewhat report large improvements in fatigue or other symptoms while others report smaller or mixed benefits, I have integrated individuals’ responses on the overall effectiveness of high-dose thiamine with their responses on its effects on individual symptoms to produce Figure 1.

As shown there, nearly two-thirds (65.5 percent) of respondents report either that high-dose thiamine has helped them a great deal overall or that one or more symptoms improved “a lot” without any symptom worsening (which I define as a large improvement).

Another 5.5 percent report that high-dose thiamine has improved certain symptoms “a little” (which I define as a small improvement).  14.5 percent report no improvement, 9.1 percent report a mix of improvements and worsening of different symptoms and 5.5 percent of respondents report that high-dose thiamine has made them feel worse.

This interpretation of the data aligns well with respondents’ reported satisfaction with high-dose thiamine on a five-point scale.  Two-thirds of respondents give high-dose thiamine the highest marks of 5 (36.4 percent) or 4 (32.7 percent), while 14.5 percent give high-dose thiamine the low marks of 2 (3.6 percent) or 1 (10.9 percent).  The remaining 16.4 percent give high-dose thiamine a middle grade of 3 out of 5.

Before exploring the specifics of the survey results, it is helpful to review respondents’ overall comments on high-dose thiamine.  Below, I excerpt selected comments on high-dose thiamine from those reporting positive effects and then from those who report experiencing no effect, mixed results or feeling worse from high-dose thiamine.  A complete set of comments by survey respondents may be found here.

Excerpts from comments by respondents who report that high-dose thiamine helped them:

  • “The thiamine has been a game-changer, it has increased energy, greatly improved cognition and cleared brain fog, increased exercise and muscle endurance and improved some random possibly autonomic symptoms. If I could have only one supplement, it would be thiamine.”
  • “It has improved my mental abilities greatly. I would crash from just conversations or thinking about something stimulating otherwise. Much greater mental and mood stability. Focus and memory.”
  • “I was bedridden and have regained 75% of normal functioning with thiamine.”
  • “One of the most helpful things for CFS/PEM. I could tell it was working the day following the first time I tried a 300 mg dose, then upped the dosage to that based on a study for IBS/Chron’s even though I do not have these or symptoms of these.”
  • “After having severe fatigue for 28 years I am getting some help with this.”
  • “It has helped my head pressure and daily dull headache… also my weak muscles in my calves feel stronger. The head pressure change is most welcomed!”
  • “It helped so much I’m staying on it. My healthy husband (who is normally spectacularly in observant about his own health) volunteered, without even knowing I’d given it to him for a few days, that his memory had improved.”
  • “After taking a supplement called Parasym Plus [whose first ingredient is thiamine] my life changed drastically for the better, I felt as if I was in a fog for 6 years and it was very scary, almost immediately after taking it I felt as if the fog had lifted, I could think more clearly, got my sense of direction back and was able to drive again, I had the energy sit up through an entire movie with I couldn’t do for years, it also helped tremendously with chronic edema in my legs!”
  • “I used it because I had ME/CFS and had a lot of problems processing alcohol and formaldehyde (which made me really sick), I saw a massive improvement.”
  • “My miracle is allithiamine- began 3/2020 and then in the month of August 2020 my high heart rate / POTS went down significantly… I just never gave up searching and wow am I so happy. The fatigue is still constant but the brain/neuroinflammation is improved significantly.”
  • “After a decade deteriorating, accelerated by covid mildly 12m ago, I seem to have stabilized and the thiamine coincided with an improvement in brain fog.”

Excerpts from comments by respondents reporting no effects, mixed results or feeling worse from high-dose thiamine

  • “I wish B1 would have been a miracle drug but it hasn’t seemed to do anything for me or if it has maybe I would have been worse than I am now.”
  • “Seemed to improve carbohydrate tolerance and made me feel relaxed. A feeling that is super rare for me since getting POTS. Effect diminishes after a few days as though my body builds tolerance.”
  • “I wish I could get it to work again. Imagine going from housebound to playing a bit of tennis. Unfortunately, after a couple of decades, my body wasn’t really ready for that and I injured myself often. I wish I knew why it stopped working.”
  • “Would like to know if there is any alternative to thiamin which will work at normal doses. I am scared of taking high doses of thiamin due to long-term side effects possible.”

Now on to the details of the survey findings.

Survey Sample

Fifty-eight percent of people responded to the survey through May 9, 2021, of which 55 met the criteria for inclusion, which were reporting one or more of three conditions (ME/CFS, Fibromyalgia, or EDS) and taking 200 mg or more daily of thiamine.  All but 7 of the survey responses came between April 15 and May 9, 2021, with the balance coming in the prior year.  Seventy-six percent of respondents identify as female, while 24 percent identify as male.  Respondents report starting high-dose thiamine between ages 20 to 81, with a median age of 50.

Of the 55 respondents, 49 report having ME/CFS, 20 report having Fibromyalgia, and 12 report having EDS.  Just over half (28) report Postural Orthostatic Tachycardia Syndrome (POTS) / Dysautonomia, while a bit more than one-quarter (15) report Mast Cell Activation Syndrome (MCAS). Eleven respondents report intracranial hypertension, 9 report cervical or atlantoaxial instability, and 7 report a CSF leak.  For purposes of these statistics, I have not distinguished between formal diagnoses and self-reports.

The Gist

  • 55 people with ME/CFS, Fibromyalgia or Ehlers-Danlos Syndrome submitted qualifying responses to a Health Rising survey on high-dose thiamine (defined as 200 mg or more daily).
  • Nearly two-thirds (65.5%) report a large improvement, and another 5.5% report a small improvement from high-dose thiamine.
  • The most commonly reported improvements are reductions in fatigue, post-exertional malaise and brain fog.
  • 5% of respondents report no improvement, 9.1% mixed results, and 5.5% report high-dose thiamine made them feel worse.
  • Respondents report benefits in each of the dosage ranges examined.
  • A more rigorous study is needed to definitively evaluate the potential of high-dose thiamine to help people in our communities.

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Type and Amount of Thiamine Taken

I limited the survey to people who report having taken 200 mg or more of thiamine daily to avoid the inclusion of the many people who take thiamine only through B Complex Vitamin supplements, which often include large amounts of thiamine (though generally less than 200 mg).  This is not because I have any reason to suspect that 200 mg daily is the minimum amount of thiamine needed to be effective – to the contrary, a newly released study (in preprint) suggests that administration of 100 mg of thiamine daily was associated with a substantial reduction in mortality among critically ill COVID-19 patients.  Rather, it was because it would be impossible to disentangle the effects of high doses of thiamine from the high doses of Vitamin B12, biotin, and the many other B vitamins included in B complex vitamins.

Dose

Survey respondents report a range of dosages, with a median of 600 mg and an average of 865 mg of thiamine daily.  Just over one-quarter of the sample report taking 200-499 mg daily of thiamine, while another one-quarter take 1,500 mg daily or more, with the balance falling in between.  The most common dosages are 600 mg (9 respondents) followed by 500 mg and 1,500 mg daily (7 respondents each).

One survey respondent reports experiencing large benefits from 100 mg daily of thiamine; that response was excluded from the overall statistics to adhere to the study protocol.  In comments on my original study, at least one individual also reported benefitting from 100 mg daily of thiamine.  Further research is needed to determine what benefits might accrue at different doses of thiamine above the formal FDA recommendation.

Type

Nearly half (49.1 percent) of respondents report using oral thiamine hydrochloride, the thiamine form used in most of the studies of high-dose thiamine to date, while 18.2 percent report using oral benfotiamine, 10.9 percent report using oral thiamine mononitrate, and another 5.5 percent report using generic oral thiamine, which is often thiamine mononitrate. The remaining 18.2 percent report using a wide range of thiamine forms including allithiamine, lipothiamine, sulbutiamine, TPP, thiamine tetrahydrofurfuryl disulfide, coenzymated thiamine, thiamax, and thiamine HCL IM.  Several respondents report combining multiple forms of thiamine; those responses have been included in the latter grouping of “other” responses, even when they report using one of the thiamine forms listed separately.

Duration

45.4 percent of respondents report taking high-dose thiamine for 6 months or more, while 12.7 percent report taking high-dose thiamine for 3 to 6 months. Just over one-quarter (27.3 percent) report taking thiamine for three weeks or less, with the balance falling between 3 weeks and 3 months.  Thirty respondents (60.8 percent of respondents answering the question) report they are still taking high-dose thiamine.  Four additional respondents (7.8 percent) report that they are now taking a daily dose below 200 mg.

Reported Improvements

As shown in Figure 2, most study respondents report substantial benefits from high-dose thiamine.  The three most commonly reported benefits are improvements in fatigue, post-exertional malaise, and brain fog.  I added brain fog to the survey midway through once respondents began mentioning it spontaneously in the comments; the adjusted levels estimate what the response would have been had brain fog been included in the survey the entire time through straight extrapolation.

More than 40 of the 55 respondents report improvements in fatigue and more than 35 report benefits from post-exertional malaise and brain fog (as adjusted). For all three symptoms, more people report that symptoms improved “a lot” than report that symptoms improved “a little.” At least one person in each category even reports the symptom went away entirely.  Other symptoms with more than 10 of the 55 respondents reporting improvements include: other pain, dizziness/lightheadedness, insomnia, neck pain, headaches, and vision issues.

In addition to the symptomatic improvements captured by the survey, two respondents report benefits for dysautonomia / heart rate:

  • “Whereas before my BP and HR were all over the place (hyperPOTS – low pressure, high pressure, bradycardia tachycardia), now I’m only ‘stuck with orthostatic hypertension and the tachycardia. I don’t black out anymore and my BP and HR don’t drop too low with B1.”
  • “While it helps with PEM, I find that the best way to avoid PEM is to pace. B1 helps me pacing, because it brings down the tachycardia and I’m able to be upright for longer. i.e. – I can cook, with breaks or take a shower, etc. Pacing pacing.”

One respondent reports improvement in light and noise sensitivity, while another reports improvement in edema.  Along with improvements in brain fog, one respondent, quoted toward the beginning of this post, reports improvements in mental abilities and mood and mental stability.  Two respondents mention improvements in memory. One respondent mentions taking high-dose thiamine for neuropathic pain.

 

Reported Worsening of Symptoms and Side Effects

Figure 3 shows respondents’ reports of worsening of these same symptoms. Fewer than 5 people report that any particular symptom became worse, with the largest numbers reporting a worsening in headaches (4) and mast cell activation (4). Three of the 4 people who identified MCAS as a problem said the issue became substantially worse, suggesting that caution be exercised by people with severe MCAS or with an MCAS flare-up.  (As noted below, however, 73% of the people with MCAS that responded to the survey report large improvements from high-dose thiamine.) One additional individual reports experiencing headaches, but they went away upon splitting the dose during the day.

Figure 4 shows respondents’ reports of the five side effects for which responses were specifically requested.  Twelve people report having trouble falling asleep from high-dose thiamine, though the problem went away for 7.  A few people report taking the last dose of the supplement before 5 p.m. in order to avoid insomnia, which matches the advice given by Dr. Antonio Costantini, one of the pioneers of this treatment. Nine people report having trouble staying asleep, with most of them reporting it as a moderate problem that persists. 8 to 9 people also report tachycardia and arrhythmia, mostly as a moderate problem that persists.  Only one person identifies any of these side effects as serious.

In addition to the responses shown in Figure 4, three individuals report stomach issues, one identifying the issue as severe, one describing it as “stomach irritation,” and a third saying the issue went away after splitting the dose during the day. One individual stopped using high-dose thiamine, despite experiencing large benefits, due to rectal bleeding; the individual notes experiencing this symptom from many different supplements.

One individual reports getting vertigo and being unable to walk straight, but the individual resolved the problem by lowering the dose. One individual reports drying of the skin, another reports jitteriness that went away, one notes diarrhea, and another notes “significant mouth/tongue pain and irritation.”

Several individuals report that high-dose thiamine stopped working for them after a period of time.  One individual found they could wait a while and then restart it successfully, while another tried this and found it unsuccessful.

What accounts for the variability in reported effects?

It is impossible to say for sure why some people appear to have benefitted from high-dose thiamine, while others appear to not have benefitted.  But the survey did include several dimensions that can be analyzed for potential clues.  Given the small sample size, non-representative sample, and my limited statistical skills, I did not do any sophisticated statistical analysis.  But I did examine a few cross-tabulations that I report on below.

Type of Condition

As shown in the top panel of Figure 5, more than 70 percent of people who identify as having each of the following conditions report improvements from high-dose thiamine: ME/CFS, fibromyalgia, EDS, and MCAS. While not shown in the table, the same is true for people who identify as having a CSF leak and cervical or atlantoaxial instability.  A smaller percentage (57.1 percent) of people who identify as having POTS / dysautonomia report benefiting from high-dose thiamine.  All of these categories are overlapping, with individual respondents able to be included in more than one category.

To investigate the POTS results further, I created four exclusive categories (i.e., in which each person can only be listed once) and report on the results in the bottom panel of Figure 5.  The four categories are:

  1. people who identify as having EDS;
  2. people who identify as having fibromyalgia but not EDS;
  3. people who identify as having ME/CFS but not EDS, fibromyalgia or POTS; and
  4. people who identify as having ME/CFS and POTS but not EDS or fibromyalgia.

While the number of respondents within each category is small, and so differences could be due to chance, the results for the last category appear quite different from the results of all the other categories.  Among people who identify as having ME/CFS and POTS but not EDS or Fibromyalgia, 40 percent report no improvement whatsoever, a much higher percentage than any other category (see bolded cell in the last row).  Perhaps a group of people within this sub-category needs a different treatment approach?

Figure 5: Reported Effects by Condition
Number Improvement No Improvement Mixed Results Got Worse
Overlapping Categories
ME/CFS 49 71.4% 16.3% 6.1% 6.1%
Fibromyalgia 20 80.0% 5.0% 10.0% 5.0%
Ehlers-Danlos Syndrome (EDS) 12 75.0% 0.0% 8.3% 16.7%
MCAS 15 73.3% 6.7% 13.3% 6.7%
POTS / Dysautonomia 28 57.1% 21.4% 14.3% 7.1%
Exclusive Categories
Ehlers-Danlos Syndrome (EDS) 12 75.0% 0.0% 8.3% 16.7%
Fibromyalgia without EDS 15 80.0% 6.7% 13.3% 0.0%
ME/CFS without EDS or Fibromyalgia
     Without POTS 13 84.6% 7.7% 0.0% 7.7%
     With POTS 15 46.7% 40.0% 13.3% 0.0%

The EDS category has the largest percentage of people who report feeling worse after taking thiamine, but this represents only two individuals and there are potential explanations for both cases.  One reports taking 600 mg of intramuscular thiamine, which far exceeds the dosage recommendations from Dr. Costantini for that form.  (See discussion below).  The second individual reports having a CSF leak, which can lead to alternating periods of intracranial hypo- and hypertension.

In general, I would expect people with intracranial hypertension to benefit from a carbonic anhydrase inhibitor and people with intracranial hypotension to potentially feel worse from the same agent.  One respondent addresses this tension specifically: “It’s a balancing act. When I have acute symptoms of spinal CSF leaks and positional headache, I need to avoid large doses of B1. However, large doses might be helpful when the body “overreacts” and overproduces CSF when the leak is healing and not leaking as much.”

Daily Dose

Figure 6 examines how reported effects vary by daily dose among those reporting using oral thiamine.  As shown there, large shares of people within each of the four-dose ranges examined report improvements from high-dose thiamine.  It is interesting to see strong results reported by people taking 200-499 mg daily as the protocol that has been researched to date focuses on a daily dose between 600 and 1,800 mg, varied by weight and gender.  It would be useful for future research to consider if benefits can be achieved for people with ME/CFS, Fibromyalgia, and EDS at doses below those used in prior research.

Figure 6: Reported Effects by Daily Dose of Oral Thiamine
 

 

Number Improvement No Improvement Mixed Got Worse
200-499 mg 15 73.3% 6.7% 13.3% 6.7%
500-600 mg 15 73.3% 20.0% 6.7% 0.0%
601-1499 mg 10 70.0% 10.0% 20.0% 0.0%
1500+mg 14 71.4% 21.4% 0.0% 7.1%

If results vary by condition, as suggested in the prior section, multivariate analysis would be needed to fully unpack any relationship between dose and different kinds of symptom improvements.  A larger sample and better controls for other variations among sample members would also be helpful.

The experience of my daughter – who has EDS, craniocervical instability and Chiari malformation – may be relevant here.  In ramping up from 300 mg to 1,800 mg daily over time, she experienced an almost immediate improvement in post-exertional malaise, followed by what felt like dose-dependent improvements in visual and mental acuity as we increased the dose.

In my prior post, I suggested high-dose thiamine might work through several mechanisms, and it seems plausible that one mechanism – such as increased cellular oxygen due to the production of carbon dioxide – might take effect toward the lower end of the dose range and another mechanism – such as reduction in cerebral spinal fluid – might become more impactful at higher doses.

Over time, it has seemed that my daughter needs a smaller dose to derive equivalent benefit; she is now taking 1,125 mg daily.  Perhaps there is also a cumulative benefit that allows for maintenance at a lower dose?

Type of thiamine and combinations with other substances

Figures 7a-7c  show reported outcomes by thiamine form for the three most commonly reported forms, grouping thiamine mononitrate and generic thiamine together.

 

Outcomes were most consistently positive for those taking benfotiamine and the combined group of thiamine mononitrate and generic thiamine, but I would not read too much into this since the numbers within each of those groups are small and these results could easily be affected by other variables, such as the medical conditions and diagnoses of those who took different forms of thiamine.

Instead, I would argue the evidence suggests that all three forms of thiamine have at least the potential to be effective.  Further research would be needed to determine if one form is more effective than others as a whole or for particular groups.

Several survey respondents comment about their choice of a particular type of thiamine.  One individual reports feeling better on thiamine hydrochloride than benfotiamine, while another reports the opposite.  One respondent reports feeling worse on thiamine hydrochloride and benfotiamine, but much better on TPP. One indicates that allithiamine is the form that worked best for them.  Several respondents report combining two to four different forms of thiamine each day.  Several individuals mention finding Dr. Lonsdale’s writing helpful in understanding the potential benefits of different forms of thiamine. Several individuals report feeling their benefits were due to taking one of the more specialized forms of thiamine (see discussion of thiamine type above); however, there were too few results for any one of these forms to analyze and report here.

One individual reports feeling somewhat worse after taking 600 mg of thiamine HCL IM. Presumably this refers to intramuscular thiamine hydrocholoride.  A website associated with Dr. Costantini’s team on the use of high-dose thiamine for Parkinson’s disease suggests that one intramuscular injection of 100 mg of thiamine HCL per week is the equivalent of taking 2 grams of oral thiamine HCL daily for a week.  If this information on equivalencies is accurate, the amount of thiamine HCL IM reported by this individual far exceeds in potency the amounts taken by other respondents or recommended by Costantini’s team.

Many respondents offer advice about combining thiamine with other supplements to maximize impact.  Several respondents express the view that thiamine works best in combination with the other B vitamins, while another notes that thiamine is effective only when taken on its own, without other B vitamins (and without other vitamins). One respondent notes benefitting from niacin, another from B12. One individual combines thiamine with Diamox (acetazolamide) as a way of reducing the amount of Diamox needed to achieve a similar effect. These and the other recommendations provided by survey respondents, along with a copy of the survey instrument, may be accessed here.

What happens next?

I have taken this research as far as I can as a non-expert.  I am hoping medical researchers and practitioners can take things from here.  I see three important next steps:

1.  Assess whether thiamine is a carbonic anhydrase inhibitor in vivo as predicted in vitro. This would help clarify what cautions need to be applied to the use of high-dose thiamine and possibly inform medical treatment of intracranial hypertension and other acetazolamide-responsive conditions

2.  Assuming thiamine is a carbonic anhydrase inhibitor, publish guidance on how to use it safely. Many people are already using high-dose thiamine and others will likely start.  It will be important for clear guidance to be available from a medical expert on how to reduce adverse drug interactions and side effects, such as hypokalemia and kidney stones.  Hopefully, patients’ medical providers can provide guidance on these questions.  But some may struggle to find doctors who are open to considering high-dose thiamine as a carbonic anhydrase inhibitor and aware of the possible interactions among supplements commonly used by people with ME/CFS, Fibromyalgia and EDS. It will be useful for the guidance to also address what to do in the event that high-dose thiamine stops working, a problem that several respondents report in this study.  As I mentioned in my earlier column, several older studies addressed this issue in the context of acetazolamide, recommending the temporary administration of sodium or potassium bicarbonate.

(While I have no medical training and cannot provide medical advice, I would note that my daughter has found it helpful to accompany high-dose thiamine with increased fluid intake.  In addition to addressing the mild diuresis of a carbonic anhydrase inhibitor, this is one of the steps Dr. Frederic Coe, Medical Director of the Kidney Stone Prevention Program at the University of Chicago, suggests to prevent formation of calcium phosphate kidney stones.)

3.  Conduct a large, randomized study of high-dose thiamine to definitively assess its effectiveness in relieving different symptoms for people with ME/CFS, Fibromyalgia and EDS. Ideally, the study would include a rich set of information on the baseline characteristics of participants, including the markers of hypermobility and intracranial hypertension collected in this 2020 study.  It might be useful to study different doses of high-dose thiamine to see whether there are better or different outcomes at each dose.

Conclusion

In conclusion, a huge thank you to everyone who completed the survey!  I hope it will be helpful for prompting future research.  I look forward to discussing the findings with anyone who wishes to comment on this post.  I would be happy to speak with researchers interested in studying this treatment further.

If high-dose thiamine is a carbonic anhydrase inhibitor as predicted by an in vitro study, it is a serious drug and should be approached cautiously.  I would recommend that individuals interested in trying high-dose thiamine discuss with their medical providers if this is a safe treatment option for them given their individual circumstances and other medications and supplements.

 

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